The three 5HT2 receptors have been implicated in many disease states, including drugs of abuse such as hallucinogens. However, their close similarity has hindered the development of truly subtype-selective ligands. Novasite has developed proprietary SAR algorithms that, by analyzing the effects of related compounds on mutants of a receptor, can identify specific ligand-receptor interactions. Novasite can generate and screen hundreds of mutants of the 5HT2 receptors, focused on exchanging subtype-selective amino acids among subtypes. Our SAR approach will then identify the chemical moieties within the ligand that interact with 5HT2 (A,B,C) subtype selective residues. Chemical derivatization of these moieties would be expected to confer subtype selective recognition, thus guiding the development of subtype-selective ligands. Our algorithm is equally powerful for identifying specific ligand-receptor interactions involving residues within the divergent extracellular loops, key determinants of subtype-selective recognition. Molecular models of the receptors will be used to analyze the SAR data. We will focus on Ergot alkaloid ligands such as LSD and Mesulergine, which have high affinity and selectivity towards the 5HT2R class relative to other GPCRs. The information derived will guide our efforts to develop 5HT2 subtype-selective ergot alkaloid ligands, which may become powerful new drug candidates. [unreadable] [unreadable]